Genome-wide association studies in amyotrophic lateral sclerosis.
Ontology highlight
ABSTRACT:
SUBMITTER: Dupre N
PROVIDER: S-EPMC2986052 | biostudies-literature | 2009 Feb
REPOSITORIES: biostudies-literature
Publications
Genome-wide association studies in amyotrophic lateral sclerosis.
Dupré Nicolas N Valdmanis Paul P
European journal of human genetics : EJHG 20081105 2
Similar Datasets
Project description:<p>The cause of sporadic amyotrophic lateral sclerosis (ALS) is unknown. To identify the genetic factors underlying this fatal neurodegenerative disease, we performed a series of genome-wide association studies of ALS. These studies are divided into three distinct stages, each associated with a separate data release. A description of each stage is provided below.</p> <p>In the first stage, we genotyped 555,352 SNPs in 276 US cases diagnosed with ALS and 271 US controls. These samples were obtained from the National Institute of Neurological Disorders and Stroke (NINDS) DNA Repository at Coriell. The 276 US cases were genotyped on Illumina HumanHap550v1.1 SNP arrays, whereas the 271 US controls were genotyped on both Illumina HumanHap250Sv1.0 and Illumina HumanHap300v1.1 SNP arrays. The genotype data was released in June 2008 under the accession number <a href="./study.cgi?study_id=phs000101.v1.p1">phs000101.v1.p1</a> and was associated with the following publication: Schymick JC et al. (2007) <a href="http://www.ncbi.nlm.nih.gov/pubmed/17362836" target="_blank">Genome-wide genotyping in amyotrophic lateral sclerosis and neurologically normal controls: first stage analysis and public release of data</a>. <i>Lancet Neurology</i> 6:322-8.</p> <p>In the second stage, we extended our genotyping to a larger cohort to identify risk factors with lower effect size. This portion of the project used a two-step approach: in step A, 545,066 SNPs were genotyped in 553 individuals with ALS and 2,338 controls. Of note, this cohort included data from the 276 US cases and 271 US controls that had been previously released in the first stage, <a href="./study.cgi?study_id=phs000101.v1.p1">phs000101.v1.p1</a>. The additional 277 ALS cases that were newly genotyped in this stage were collected in a population-based manner from the North of Italy and were genotyped on Illumina HumanHap550v1.1 SNP arrays. In step B, we brought forward the 7,600 most associated SNPs from step A, and genotyped them in an additional cohort consisting of 2,160 cases and 3,008 controls using an Illumina iSelect custom designed SNP array. The new data generated from this study was released in May 2010 (<a href="./study.cgi?study_id=phs000101.v2.p1">phs000101.v2.p1</a>) and consisted of 1,456 case samples and 773 control samples for which participants provided consent to make their data publicly available. We do not have permission to publicly release the genotype data from the rest of the samples. This data release was associated with the following publication: Chiò A et al. (2009) <a href="http://www.ncbi.nlm.nih.gov/pubmed/19193627" target="_blank">A two-stage genome wide association study of sporadic amyotrophic lateral sclerosis</a>. <i>Human Molecular Genetics</i> 18:1524-32.</p> <p>In the third stage, we genotyped 601,273 SNPs in an additional set of 236 Italian ALS cases. Together with the 264 Italian samples genotyped as part of stage 2, this brought the total number of samples that were whole genome genotyped samples to 504. These additional 236 patients had been collected in a population-based manner from the Piedmonte region in the North of Italy, and were genotyped using Illumina Human610Quad.v1 SNP arrays. The rational for this stage of the study arose from a <i>Proceedings of the National Academy of Sciences (PNAS)</i> publication by Landers et al. 2009, hypothesizing that genetic variation on chromosome 1q24 in the vicinity of the KIFAP3 gene was associated with a significant improvement in survival of ALS patients. Our data failed to replicate this finding suggesting that the original finding may have been a false positive finding. The data generated for the extra 236 Italian ALS cases used in this study was released in April 2011 (<a href="./study.cgi?study_id=phs000101.v3.p1">phs000101.v3.p1</a>). This data release was associated with the following publication: Traynor BJ et al. (2010) <a href="http://www.ncbi.nlm.nih.gov/pubmed/20566859" target="_blank">Kinesin-associated protein 3 (KIFAP3) has no effect on survival in a population-based cohort of ALS patients</a>. PNAS 107:12335-8. Of note, 95 of these 236 samples had also been genotyped on the Illumina iSelect custom designed SNP array used in the second stage of this study (see README.txt file available through dbGaP Authorized Access for list of the 95 samples).</p> <p>This study utilized the <a href="./study.cgi?id=phs000006">NINDS Repository Motor Neuron Disease/ALS Study</a>, and <a href="./study.cgi?id=phs000004">neurologically normal controls</a> from the sample population which are banked in the National Institute of Neurological Disorders and Stroke (NINDS Repository) collection.</p>
| phs000101.v3.p1 | EGA
Project description:The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown, but genetic factors are thought to play a significant role in determining susceptibility to motor neuron degeneration. To identify genetic variants altering risk of ALS, we undertook a two-stage genome-wide association study (GWAS): we followed our initial GWAS of 545 066 SNPs in 553 individuals with ALS and 2338 controls by testing the 7600 most associated SNPs from the first stage in three independent cohorts consisting of 2160 cases and 3008 controls. None of the SNPs selected for replication exceeded the Bonferroni threshold for significance. The two most significantly associated SNPs, rs2708909 and rs2708851 [odds ratio (OR) = 1.17 and 1.18, and P-values = 6.98 x 10(-7) and 1.16 x 10(-6)], were located on chromosome 7p13.3 within a 175 kb linkage disequilibrium block containing the SUNC1, HUS1 and C7orf57 genes. These associations did not achieve genome-wide significance in the original cohort and failed to replicate in an additional independent cohort of 989 US cases and 327 controls (OR = 1.18 and 1.19, P-values = 0.08 and 0.06, respectively). Thus, we chose to cautiously interpret our data as hypothesis-generating requiring additional confirmation, especially as all previously reported loci for ALS have failed to replicate successfully. Indeed, the three loci (FGGY, ITPR2 and DPP6) identified in previous GWAS of sporadic ALS were not significantly associated with disease in our study. Our findings suggest that ALS is more genetically and clinically heterogeneous than previously recognized. Genotype data from our study have been made available online to facilitate such future endeavors.
| S-EPMC2664150 | biostudies-literature
Project description:BackgroundThe genetic cause of amyotrophic lateral sclerosis (ALS) is not well understood. Finland is a well suited location for a genome-wide association study of ALS because the incidence of the disease is one of the highest in the world, and because the genetic homogeneity of the Finnish population enhances the ability to detect risk loci. We aimed to identify genetic risk factors for ALS in the Finnish population.MethodsWe did a genome-wide association study of Finnish patients with ALS and control individuals by use of Illumina genome-wide genotyping arrays. DNA was collected from patients who attended an ALS specialty clinic that receives referrals from neurologists throughout Finland. Control samples were from a population-based study of elderly Finnish individuals. Patients known to carry D90A alleles of the SOD1 gene (n=40) were included in the final analysis as positive controls to assess whether our genome-wide association study was able to detect an association signal at this locus.FindingsWe obtained samples from 442 patients with ALS and 521 control individuals. After quality control filters were applied, 318 167 single nucleotide polymorphisms (SNPs) from 405 people with ALS and 497 control individuals were available for analysis. We identified two association peaks that exceeded genome-wide significance. One was located on chromosome 21q22 (rs13048019, p=2·58×10(-8)), which corresponds to the autosomal recessive D90A allele of the SOD1 gene. The other was detected in a 232 kb block of linkage disequilibrium (rs3849942, p=9·11×10(-11)) in a region of chromosome 9p that was previously identified in linkage studies of families with ALS. Within this region, we defined a 42-SNP haplotype that was associated with significantly increased risk of ALS (p=7·47×10(-33) when people with familial ALS were compared with controls, odds ratio 21·0, 95% CI 11·2-39·1) and which overlapped with an association locus recently reported for frontotemporal dementia. For the 93 patients with familial ALS, the population attributable risk for the chromosome 9p21 locus was 37·9% (95% CI 27·7-48·1) and that for D90A homozygosity was 25·5% (16·9-34·1).InterpretationThe chromosome 9p21 locus is a major cause of familial ALS in the Finnish population. Our data suggest the presence of a founder mutation for chromosome 9p21-linked ALS. Furthermore, the overlap with the risk haplotype recently reported for frontotemporal dementia provides further evidence of a shared genetic cause for these two neurodegenerative diseases.FundingNational Institutes of Health and National Institute on Aging, Microsoft Research, ALS Association, Helsinki University Central Hospital, Finnish Academy, Finnish Medical Society Duodecim, and Kuopio University.
| S-EPMC2965392 | biostudies-literature
Project description:Genome-wide association studies (GWAS) have identified multiple causal genes associated with amyotrophic lateral sclerosis (ALS); however, the genetic architecture of ALS remains completely unknown and a large number of causal genes have yet been discovered. To full such gap in part, we implemented an integrative analysis of transcriptome-wide association study (TWAS) for ALS to prioritize causal genes with summary statistics from 80,610 European individuals and employed 13 GTEx brain tissues as reference transcriptome panels. The summary-level TWAS analysis with single brain tissue was first undertaken and then a flexible p-value combination strategy, called summary data-based Cauchy Aggregation TWAS (SCAT), was proposed to pool association signals from single-tissue TWAS analysis while protecting against highly positive correlation among tests. Extensive simulations demonstrated SCAT can produce well-calibrated p-value for the control of type I error and was often much more powerful to identify association signals across various scenarios compared with single-tissue TWAS analysis. Using SCAT, we replicated three ALS-associated genes (i.e., ATXN3, SCFD1, and C9orf72) identified in previous GWASs and discovered additional five genes (i.e., SLC9A8, FAM66D, TRIP11, JUP, and RP11-529H20.6) which were not reported before. Furthermore, we discovered the five associations were largely driven by genes themselves and thus might be new genes which were likely related to the risk of ALS. However, further investigations are warranted to verify these results and untangle the pathophysiological function of the genes in developing ALS.
| S-EPMC7714931 | biostudies-literature
Project description:ImportanceConsiderable advances have been made in our understanding of the genetics underlying amyotrophic lateral sclerosis (ALS). Nevertheless, for the majority of patients who receive a diagnosis of ALS, the role played by genetics is unclear. Further elucidation of the genetic architecture of this disease will help clarify the role of genetic variation in ALS populations.ObjectiveTo estimate the relative importance of genetic factors in a complex disease such as ALS by accurately quantifying heritability using genome-wide data derived from genome-wide association studies.Design, setting, and participantsWe applied the genome-wide complex trait analysis algorithm to 3 genome-wide association study data sets that were generated from ALS case-control cohorts of European ancestry to estimate the heritability of ALS. Cumulatively, these data sets contained genotype data from 1223 cases and 1591 controls that had been previously generated and are publically available on the National Center for Biotechnology Information database of genotypes and phenotypes website (http://www.ncbi.nlm.nih.gov/gap). The cohorts genotyped as part of these genome-wide association study efforts include the InCHIANTI (aging in the Chianti area) Study, the Piemonte and Valle d'Aosta Register for Amyotrophic Lateral Sclerosis, the National Institute of Neurological Disorders and Stroke Repository, and an ALS specialty clinic in Helsinki, Finland.Main outcomes and measuresA linear mixed model was used to account for all known single-nucleotide polymorphisms simultaneously and to quantify the phenotypic variance present in ostensibly outbred individuals. Variance measures were used to estimate heritability.ResultsWith our meta-analysis, which is based on genome-wide genotyping data, we estimated the overall heritability of ALS to be approximately 21.0% (95% CI, 17.1-24.9) (SE = 2.0%), indicating that additional genetic variation influencing risk of ALS loci remains to be identified. Furthermore, we identified 17 regions of the genome that display significantly high heritability estimates. Eleven of these regions represent novel candidate regions for ALS risk.Conclusions and relevanceWe found the heritability of ALS to be significantly higher than previously reported. We also identified multiple, novel genomic regions that we hypothesize may contain causative risk variants that influence susceptibility to ALS.
| S-EPMC4566960 | biostudies-literature
Project description:Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with strong genetic components. To identity novel risk variants for ALS, utilizing the latest genome-wide association studies (GWAS) and eQTL study data, we conducted a genome-wide expression association analysis by summary data-based Mendelian randomization (SMR) method. Summary data were derived from a large-scale GWAS of ALS, involving 12577 cases and 23475 controls. The eQTL annotation dataset included 923,021 cis-eQTL for 14,329 genes and 4732 trans-eQTL for 2612 genes. Genome-wide single gene expression association analysis was conducted by SMR software. To identify ALS-associated biological pathways, the SMR analysis results were further subjected to gene set enrichment analysis (GSEA). SMR single gene analysis identified one significant and four suggestive genes associated with ALS, including C9ORF72 (P value = 7.08 × 10-6), NT5C3L (P value = 1.33 × 10-5), GGNBP2 (P value = 1.81 × 10-5), ZNHIT3(P value = 2.94 × 10-5), and KIAA1600(P value = 9.97 × 10-5). GSEA identified 7 significant biological pathways, such as PEROXISOME (empirical P value = 0.006), GLYCOLYSIS_GLUCONEOGENESIS (empirical P value = 0.043), and ARACHIDONIC_ACID_ METABOLISM (empirical P value = 0.040). Our study provides novel clues for the genetic mechanism studies of ALS.
| S-EPMC11481841 | biostudies-literature
Project description:Genome-wide association study of amyotrophic lateral sclerosis in Finland
| PRJNA75849 | ENA
Project description:BackgroundEpidemiological and clinical studies have suggested comorbidity between amyotrophic lateral sclerosis (ALS) and autoimmune disorders. However, little is known about their shared genetic architecture.MethodsTo examine the relation between ALS and 10 autoimmune diseases, including asthma, celiac disease (CeD), Crohn's disease (CD), inflammatory bowel disease (IBD), multiple sclerosis (MS), psoriasis, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), and ulcerative colitis (UC), and identify shared risk loci, we first estimated the genetic correlation using summary statistics from genome-wide association studies, and then analyzed the genetic enrichment leveraging the conditional false discovery rate statistical method.ResultsWe identified a significant positive genetic correlation between ALS and CeD, MS, RA, and SLE, as well as a significant negative genetic correlation between ALS and IBD, UC, and CD. Robust genetic enrichment was observed between ALS and CeD and MS, and moderate enrichment was found between ALS and UC and T1D. Thirteen shared genetic loci were identified, among which five were suggestively significant in another ALS GWAS, namely rs3828599 (GPX3), rs3849943 (C9orf72), rs7154847 (G2E3), rs6571361 (SCFD1), and rs9903355 (GGNBP2). By integrating cis-expression quantitative trait loci analyses in Braineac and GTEx, we further identified GGNBP2, ATXN3, and SLC9A8 as novel ALS risk genes. Functional enrichment analysis indicated that the shared risk genes were involved in four pathways including membrane trafficking, vesicle-mediated transport, ER to Golgi anterograde transport, and transport to the Golgi and subsequent modification.ConclusionsOur findings demonstrate a specific genetic correlation between ALS and autoimmune diseases and identify shared risk loci, including three novel ALS risk genes. These results provide a better understanding for the pleiotropy of ALS and have implications for future therapeutic trials.
| S-EPMC7863260 | biostudies-literature
Project description:Amyotrophic lateral sclerosis (ALS) is a complex disease that leads to motor neuron death. Despite heritability estimates of 52%, genome-wide association studies (GWASs) have discovered relatively few loci. We developed a machine learning approach called RefMap, which integrates functional genomics with GWAS summary statistics for gene discovery. With transcriptomic and epigenetic profiling of motor neurons derived from induced pluripotent stem cells (iPSCs), RefMap identified 690 ALS-associated genes that represent a 5-fold increase in recovered heritability. Extensive conservation, transcriptome, network, and rare variant analyses demonstrated the functional significance of candidate genes in healthy and diseased motor neurons and brain tissues. Genetic convergence between common and rare variation highlighted KANK1 as a new ALS gene. Reproducing KANK1 patient mutations in human neurons led to neurotoxicity and demonstrated that TDP-43 mislocalization, a hallmark pathology of ALS, is downstream of axonal dysfunction. RefMap can be readily applied to other complex diseases.
| S-EPMC9017397 | biostudies-literature
Project description:To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
| S-EPMC5556360 | biostudies-literature